Approximately 100 million people in the United States suffer from pain with some 9 to 12 million individuals suffering from chronic or persistent pain.1 With opioids remaining at the forefront of treatment, it has become clear that opioid abuse and opioid overdose have emerged as significant and complicated public health challenges. Drug overdose from opioids is the leading cause of accidental death in the U.S. with an estimated 100 individuals a day dying from opioid overdose due to respiratory depression.2 Although multiple factors are unquestionably responsible for the increase in the use and abuse of opioids, there is a pressing need for an effective opioid analgesic that also addresses the significant issues surrounding opioid abuse liability and overdose fatalities. Advances in our understanding of the pharmacological mechanisms associated with signaling of G-protein coupled receptors have resulted in the knowledge that activation of the mu-opioid receptor (MOR) mediates both the therapeutic and adverse effects and does so through pharmacologically distinct signaling pathways. The adverse effects associated with morphine and other MOR agonists have been traced to action through the ?-arrestin pathway, while analgesia is tied to the G-protein pathway. G-protein specific agonists that avoid activation of ?-arrestin signaling and its associated negative consequences provide novel strategies for the development of pathway specific or ?biased? drugs designed to selectively produce analgesia while eliminating unwanted adverse effects that include respiratory depression, abuse liability, and constipation. Mebias Discovery LLC has developed a novel platform and has identified highly ?biased? MOR agonists that are effective analgesics but are devoid of opioid induced adverse effects. Mebias? preclinical studies compared two compounds, MEB-1166 and MEB-1170, against Trevena?s Oliceridine (TRV-130) and morphine. At a dose 4X that required to reach the efficacy equivalent to ED80 of morphine, both Mebias compounds displayed no respiratory depression, while morphine and Oliceridine significantly reduced respiratory function. In contrast to morphine, neither MEB-1166 nor MEB-1170 produced conditioned place preference, suggesting an absence of abuse liability. The research outlined in the UG3 portion of this application is based on these encouraging results collected thus far and is designed to provide a thorough evaluation of MEB-1166 and MEB-1170 to characterize their pharmaceutical and pharmacological profiles to select a candidate for IND-enabling studies. We will also conduct abuse liability studies and examine analgesic activity in a wider range of pain models. Upon completion of the UG3 portion of this proposal, we anticipate that MEB-1166 or MEB-1170 will proceed into the UH3 portion of this application conducting Phase 1 studies to examine single and multiple ascending dose studies in healthy volunteers and abuse liability in a ?Connoisseur study?. 1 Califf, Robert M., Janet Woodcock, and Stephen Ostroff. A proactive response to prescription opioid abuse. New England Journal of Medicine 374, no.15 (2016): 1480-1485. 2 Opioid overdose. Centers for Disease Control and Prevention. August 30, 2017. Accessed January 12, 2018. https://www.cdc.gov/drugoverdose/epidemic/index.html